Abstract. Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by the neurotransmitter glutamate. Such excitotoxic neuronal death has been implicated in cerebral global ischemia and is a result of excessive presynaptic glutamate release. It is believed that glutamate transmission requires import of glutamine into axon terminals from astrocytes to replenish cytoplasmic glutamate levels and vesicular stores lost following excessive synaptic glutamate release. Thus, blocking synaptic import of glutamine represents a potential therapeutic target to limit continued glutamate release under conditions of excitotoxicity. We have recently functionally identified a novel activity-regulated glutamine transporter, which is potently inhibited by the anti-glutamatergic drug riluzole. Critical barriers to progress in understanding presynaptic mechanisms involved in excessive glutamate release are 1) the molecular identity of the neuronal activity-regulated glutamine transporter expressed in synapses is not known, 2) riluzole derivatives that selectively block the neuronal activity-regulated glutamine transporter, and that have improved brain penetration, are not available, and 3) the role of the neuronal activity-regulated glutamine transporter in vivo has not been determined. Riluzole blocks excessive synaptic glutamate release and can block neuronal damage that occurs in conditions of excitotoxicity, including global cerebral ischemia in rodents. We have identified novel riluzole derivatives with superior brain penetration that potently block neuronal activity-regulated glutamine transport, but those likely do not interfere with Na+ (i.e., NaV) or K+ (i.e., KV) channels, compared to riluzole. The functional identification of riluzole-sensitive, neuronal activity-regulated glutamine transport in hippocampal synapses has important ramifications in the neurobiology of synaptic glutamate release, the glutamate/glutamine cycle, and glutamate-induced excitotoxicity. Our overall goal is to improve therapeutic options in conditions of excessive glutamate release from synapses by providing rationale for developing drugs to limit activity-driven glutamine import in axon terminals and replenishment of cytoplasmic glutamate levels required to sustain excitotoxic glutamate release.